We recently reported an autosomal-recessive mutation that causes severe combined immunodeficiency disease (scid) in the mouse. Affected mice are severely deficient in T and B lymphocytes; consequently, they have little or no immunity and readily succumb to infections by pathogenic viruses or bacteria. To ensure their survival, SCID mice must be raised and maintained in a "clean" environment, free of pathogenic microorganisms. The importance of the SCID mouse is that it enables one to study a genetic locus that controls early lymphoid differentiation and, at the same time, serves as a model for a similar disease syndrome in humans. We have shown that the scid mutation specifically blocks lymphoid differentiation and maturation. One strategy for understanding the nature of this defect is to characterize lymphoid cells representative of those arrested in the SCID mouse. Accordingly, we are analyzing early pre-B cell lines obtained by transformation of SCID bone marrow cells with the Abelson murine leukemia virus. Five Abelson lines have been analyzed to date with probes specific for the C-micro and the Jh regions of the Igh locus. All five lines show Igh rearrangements, but in all cases at least one of the Igh alleles appears to have deleted its Jh region. Such deletions are not seen in Abelson lines derived from the bone marrow of normal mice. These data suggest the Igh rearrangements in early B cells of SCID mice may be more error-prone than in normal mice. Similar analyses are planned with SCID T-cell lymphomas using analogous probes specific for the beta gene of the T-cell receptor. These lymphomas arise spontaneously in SCID mice and appear to derive from immature T cells routinely found in the thymus. A second strategy for understanding the effects of the scid lesion is to characterize lymphoid cells that escape or bypass the maturation block. The existence of such cells is inferred because serum immunoglobulin (Ig) can be detected in 10 to 15% of SCID mice. Some of these mice in fact produce 3 to 4 times the quantity of Ig found in normal mice. Whether the cells responsible are normal or abnormal is not clear, and we continue to investigate the etiology and nature of such Ig-producing cells. (LB)